1. Field of the Invention
The present invention relates to a protein marker for monitoring, diagnosis and screening of cancer, and a method for monitoring, diagnosis and screening of cancer using the same. More precisely, the invention relates to des-R-prothrombin activation peptide fragment F2 (des-R F2), the protein marker specifically down-regulated in liver cancer, breast cancer and stomach cancer patients, and a method for monitoring, diagnosis and screening of liver cancer, breast cancer and stomach cancer by the quantification of the said protein marker.
2. Description of the Related Art
Ever since Henry Bence-Jones first used the protein which was particularly precipitated in oxidized urine as a biomarker for diagnosis of multiple myeloma, numbers of tumor-related biomarkers (tumor markers, cancer markers, etc) have been developed and reported. The definition of a tumor marker is being broadened and thus different definitions have been suggested (Diamandis, E. P., et al., AACC Press, Washington D.C., pp. 3-8, 2002). However, there is a common definition of the tumor-related biomarker. That is, a tumor marker indicates a specific molecule, a material or a process that is changed in quantity or quality in pre-cancerous condition or cancerous lesions (Hayes D. F. et al., J Natl Cancer Inst 88, 1456-66, 1996). This change can be resulted from a tumor itself or from the response of normal tissues against the tumor.
In Korea, cancer incidence has increased gradually since 1970, and now cancer is the number one reason of death by disease. According to the report regarding cancer patients made by Korea National Health Insurance Cooperation in 2005, the most frequent incidence of cancer is stomach cancer, and colon cancer, lung cancer, liver cancer, and thyroid cancer followed in that order. Particularly, in male patients, stomach cancer is in the leading position and then lung cancer, liver cancer, colon cancer and prostate cancer follow, while in female patients thyroid cancer is in the leading position and then breast cancer, stomach cancer, colon cancer and lung cancer follow in that order. According to the above report, the death of cancer was 65,479 in total in 2005, indicating that cancer was recorded as the leading cause of death. Most cancers are found as progressed except prostate cancer and thyroid cancer and cure rate is around 50%. According to the research result of National Cancer Center Korea reported in 2003, direct cost paid by patients for the treatment of cancer reached 2.2 trillion won per year and if the productivity loss caused by early death and caregiver's loss was converted as costs, the total economic burden reached at least 15 trillion won per year. 56% of cancer patients lose their job after diagnosis of the disease, suggesting that cancer is the disease that damages not only personal health but also national economy greatly. In the meantime, stomach cancer demonstrates 90% of cure rate when it is early-diagnosed and breast cancer demonstrates 95% of survival rate when it is early-diagnosed. Therefore, early diagnosis of cancer not only improves cure rate significantly but also is very important in public health and national economy. Therefore, many countries make huge investment to develop a simple but accurate method for early-diagnosis. The method using prostate specific antigen (PSA) which has been used for diagnosis of prostate cancer as a marker is easy to measure PSA in serum and accordingly significantly reduces death caused by prostate cancer. Based on that, many researchers have tried to find out tumor-related biomarkers in serum.
Studies on tumor-related biomarkers (identification of a biomarker and validation thereof) are the processes that require a large amount of time and effort. There was a momentum in such studies, which was made by the completion of human genome project, high-density gene chip (DNA microarray) based techniques and proteome based high-throughput techniques.
It is well known that the method of genome analysis using gene chip plays an important role in understanding pathophysiology of cancer and identifying of a biomarker useful for diagnosis. However, the genome analysis method is critically limited because mRNA transcriptional activity cannot reflect the expression and functions of a target protein in tumor. Even though genetic information (DNA) is transcribed into RNA to produce protein, there are still numbers of complicated processes of diversity at the levels of RNA, protein translation and post-translational modification. Therefore, only when protein, the final product of DNA, is correctly analyzed (proteome), biological meaning of the target gene and corresponding protein in tumor development can be understood, the identification of a biomarker is realized, and an important clue for the development of a drug specific target can be provided.
Two-dimensional gel electrophoresis, MALDI-TOF MS (matrix-assisted laser desorption and ionization time-of-flight mass spectrometry) and SELDl-TOF (surface-enhanced laser desorption and ionization time-of-flight mass spectrometry) are the examples of recent high-throughput proteome analysis techniques. These techniques facilitate profiling of expression patterns of every protein and modified proteins in a wide range of molecular weights (Richter R. et al., J Chromotogr B Biomed Sci Appl 726, 2535, 1999; Paweletz C. P. et al., Drug Dev Research 49, 3442, 2000). SELDI-TOF MS is similar to MALDI-TOF MS, but is designed to be suitable for quantification with relatively high sensitivity and excellent reproducibility. Complicated biochemical materials can be treated by this technique and even a small amount of protein sample can also be used without purification. In addition, pre-treatment of a marker or matrix mixing processes are not necessary in this method. However, a novel marker that enables diagnosis of liver cancer, breast cancer and stomach cancer with higher accuracy and easiness is still required and a method using the same is also required.
The present inventors collected serum samples from liver cancer, breast cancer and stomach cancer patients and normal healthy people as well, followed by SELDI-TOF MS, protein sequencing, and bio-informatics analysis. As a result, the present inventors completed this invention by identifying protein markers useful for monitoring, diagnosing and screening liver cancer, breast cancer and stomach cancer.